Named for Indian fighter Lewis Wetzel, Wetzel County was created on January 10, 1846. It has an area of 361.3 square miles and a population of 14,442 in 2020.

Wetzel County lies just south of the Northern Panhandle. The county fronts the Ohio River for just over 13 miles. Most of Wetzel County falls within the watershed of Fishing Creek, which joins the Ohio at New Martinsville. The Wetzel County landscape may be described as rolling to quite hilly. The county's lowest point is located in its southwestern corner on the Ohio River at 588 feet above sea level, and its highest point is at the summit of Honsocker Knob in the northeastern corner, at 1,650 feet. Wetzel is bounded on the north by Marshall County and Greene County, Pennsylvania; to the east by Monongalia, Marion, and Harrison counties; to the south by Doddridge and Tyler counties; and to the west by the Ohio River.

Wetzel was originally part of Ohio County, which was created in 1776. In 1814, Tyler County was formed from the southern part of Ohio County. Wetzel County was formed from the northern part of Tyler County in 1846.

The first European-American settlers were primarily of German, Swiss, Scotch-Irish, and English origin, with Edward Dulin settling New Martinsville in 1773. Reader was settled in 1788 by James Troy, and the land was later sold to the town's namesake, Benjamin Reader. Proctor was named for a fur trapper who lived in a cave on Proctor Creek and was killed by Indians in the late 1700s. John Wyatt is known to have settled Pine Grove in 1790. William Ice and Aiden Bales pioneered Grant District in 1796. Obadiah Paden, of Lancaster, Pennsylvania, settled the land of present Paden City in 1796. The William Little family settled Littleton in 1797, and Henry Church settled Hundred shortly before the turn of the 19th century. Peter Bartrug settled Burton in the early 1800s, and Wileyville was established by Shannon Wiley in the latter half of that century. Folsom was settled by Henry Talkington, and Smithfield by Aiden Bales in 1796.

The main highways in Wetzel County are State Route 2, running north and south, and State Routes 7 and 20, running east and west. Rail service is provided by CSX, and the Ohio River is a vital route for transporting goods north toward Pittsburgh and south toward the Mississippi River. A small airport is located in New Martinsville, the chief town and county seat of Wetzel County.

Natural gas, petroleum, glass, marbles, timber, livestock, fruits, and vegetables remain the county's primary industries. While no heavy industry is located within the county, many residents work at the nearby Covestro (formerly Bayer) plant and PPG Industries.

Oil and gas exploration and development began with the drilling of the first gas well in 1886 in Hundred, which is still producing. Joseph Trees and Michael Benedum, leading entrepreneurs in the industry, also developed oil and gas wells in Pine Grove, Smithfield, Folsom, and Proctor. Many of these wells continue to be active today.

Regional timber stands consist mostly of hardwoods, with oak and hickory predominating. The channel, islands, floodplain, and terraces of the Ohio River provide sand and gravel to the county.

Wetzel County has high schools at New Martinsville, Pine Grove, Paden City, and Hundred, as well as several elementary schools. Wetzel County Hospital, affiliated with WVU Medicine, has 68 beds with additional accommodations for skilled nursing patients, and has three operating rooms, an emergency department, and numerous outpatient services. In 2023, Wetzel County's largest employers were the county school system, American Consolidated Natural Resources, Walmart, WVU Medicine, and Litman Excavating.

Wetzel County is popular with sportsmen. Deer, turkey, and squirrel hunting are common, and largemouth and smallmouth bass, hybrid bass, catfish, crappie, and walleye are caught in abundance.

New Martinsville enjoys the unusual advantage of having its own electricity generating plant. The hydroelectric facility at Hannibal locks and dam was completed in 1988. Now, it produces 37 megawatts from two units, and serves New Martinsville and one other city within the county with electricity. The nearby Veterans Memorial Bridge gives residents of Wetzel County easy access to Ohio.